The incidence of Crohn's Disease (CD) is increasing, especially in young children and infants, posing an increasing burden on society. (1, 2) CD is believed to be the result of a failure of tolerance induction to normal intestinal bacteria in genetically predisposed individuals.(3) Tolerance is mediated by regulatory T cells (Tregs). Few treatments seek to augment the suppressive aspects of the immune system such as Tregs. Instead, current treatments rely on modifying the immune system by inhibiting pro-inflammatory responses. These therapies can have serious side effects, especially in children whose growth and development can be permanently affected. There is an urgent need for new therapies that have less potential side effects. Few treatments have sought to utilize Tregs, and none have done so through the skin, as a therapy to suppress inflammation in the gut. Studies using the neo-antigen keyhole limpet hemocyanin have shown that CD patients have an inherent defect in the ability to form tolerance via the gut.(4, 5) Thus, attempts at inducing oral tolerance as a treatment for CD have so far not been successful,(6) and other routes to induce tolerance should be explored. Our initial studies have shown that the skin is a highly active immune organ capable of the induction of effector cells,(7) as well as immune tolerance. Work utilizing an antigen delivery system through the skin, Viaskin(r), has shown the induction of Tregs and suppression of eosinophilic intestinal inflammation.(8, 9) Our preliminary data demonstrate that tolerance and the induction of Tregs can be achieved by epicutaneous exposure. These Tregs can be found systemically, in the mesenteric lymph nodes and in the intestine and are able to suppress inflammation. We therefore propose to develop a novel, innovative approach to treat Crohn's disease by epicutaneously inducing Tregs to suppress intestinal inflammation via bystander suppression. We will perform studies determining the potential of epicutaneous tolerance induction for the treatment of CD. We will begin by examining Tregs generated via epicutaneous exposure to antigen, augmenting their homing to the gut with retinoic acid, and activating them with subsequent feeding of antigen. We will then determine if they are stable during colitis and if they function to suppress intestinal inflammation. Finally, we will determine mechanisms of colitis suppression. The central hypothesis of this application is that epicutaneous exposure to an innocuous antigen will generate tolerance and an induction of Tregs, which will control inflammation in CD via bystander suppression. Data from these purposed experiments will open a new therapeutic area for the treatment of CD, which will be examined in future clinical studies in humans.